Suberoylanilide hydroxamic acid overcomes erlotinib-acquired resistance via phosphatase and tensin homolog deleted on chromosome 10-mediated apoptosis in non-small cell lung cancer

• Published in: Chinese medical journal Vol. 133; no. 11; pp. 1304 - 1311
• Main Authors: Wu, Peng-Fei, Gao, Wei-Wei, Sun, Cui-Lan, Ma, Tai, Hao, Ji-Qing
• Format: Journal Article
• Language: English
• Published: China The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license 05.06.2020; Lippincott Williams & Wilkins Ovid Technologies; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Wolters Kluwer Health; Wolters Kluwer
• Subjects: Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Chromosomes, Human, Pair 10; Drug Resistance, Neoplasm; ErbB Receptors - genetics; Erlotinib Hydrochloride - pharmacology; Humans; Inhibitor drugs; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Mutation; Original; Polymerase chain reaction; Protein Kinase Inhibitors - pharmacology; Proteins; Radiation therapy; Software; Targeted cancer therapy; Tensins; Vorinostat - pharmacology; Xenograft Model Antitumor Assays; United States > US; Histone deacetylase; SAHA; Acquired resistance; Erlotinib; Lung cancer
• ISSN: 0366-6999; 2542-5641; 2542-5641
• DOI: 10.1097/CM9.0000000000000823

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, are widely used to treat non-small cell lung cancer (NSCLC). However, acquired resistance is unavoidable, impairing the anti-tumor effects of EGFR-TKIs. It is reported that histone deacetylase (HDAC) inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy. However, whether the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can overcome erlotinib-acquired resistance is not fully clear. An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures. NSCLC cells were co-cultured with SAHA, erlotinib, or their combination, and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting. Finally, the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was assessed by western blotting. The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line. PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells, and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells. Furthermore, treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone. PTEN deletion is closely related to acquired resistance to EGFR-TKIs, and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy. SAHA enhances the suppressive effects of erlotinib in lung cancer cells, increasing cellular apoptosis and PTEN expression. SAHA can be a potential adjuvant to erlotinib treatment, and thus, can improve the efficacy of NSCLC therapy.